Nitrophenyl ketonic amino alcohols



Patented July 18,1950

' NITROPHENIL KETONIO AMINO I ALCQHOLS I, I v Loren M. Long, Grosse Pointe Woods, Mich, as-

signor to Parke, Davis 8; Company, Detroit,

Michga corporation of Michigan No Drawing. Application July 25, 1949, SerialNoJ 6,73 1

taining these products. More' particularly the invention relates to nitrophenyl ketonic amino alcohol compounds which have in their free base form the formula,

Q-tt-dn-omon a where R1 and R2 are the same or different and represent hydrogen, halogen, lower alkyl or lower alkoxy radicals.

Due to the rather unstable nature of the free base products the preferred compounds of the invention are the acid addition salts of the nitrophenyl ketonic amino alcohol compounds with organic or inorganic acids. Some examples of these acid addition salts are the hydrochloride, hydrobromide, hydroiodide, sulfate, sulfamate, benzoate, acetate, phosphate, phthalate, citrate, succinate, maleate, tartrate, propionate and the like.

In accordance with the invention the nitrophenyl ketonic amino alcohol compounds are obtained by hydrolysis of the corresponding nitrophenyl ketonic N-acylamido alcohol or acyloxy compound of formula,

R1 0 NH-Acyl was...

continuation-in-part of as hydrochloric, hydrobromic, sulfuric, phosphoric and the like acids'are preferred.

The products of the invention are particularly usefu1 in the synthesis of organic compounds possessing antibiotic activity.

The invention is illustrated by the following examples.

Example 1 [a] 3 g. oi. p-nitro-a-acetamidoi-hydroi y- "'7 Claims. ((11.2 .4705) 'a amino-fl hydroxypropiophenone hydrochloride I of formula,

0 NHrHCl If desired, this white solid product, M. P. 182 C. after recrystallization, can be neutralized with a. weakly alkaline substance to obtain the rather unstable free base. The free base oxidizes and rapidly turns red on exposure to air.

p-Nitro-a-amino-p-hydroxypropiophenone hydrochloride can also be obtained by substituting 3 g. of p-nitro-a-acetamido-fl-acetoxypropiophenone for the free hydroxy starting material used above.

If cc. of 5% hydrobromic acid or sulfuric acid is used in the above procedure one obtains the respective hydrobromide and sulfate salts of p-nitro-a-amino-,9-hydroxypropiophenone.

[b] 50.4 g. of p-nitro-a-acetamido-p-hydroxypropiophenone in 500 cc. of 18% hydrochloric acid is heated on a steam bath for forty-five minutes and then the solution concentrated to dryness in vacuo after extraction of the solution with ethyl acetate. The solid residue which consists of p-nitro-a-amino-p-hydroxypropiophenone hydrochloride is ground with a little absolute ethanol, collected and washed with absolute ethanol; M. P. 182 C. dec. Recrystallization from hot absolute ethanol [1 g. per 50 cc.] raises the melting point to l82-3 C.

Example 2 011a and can be purified by recrystallization from absolute ethanol. tained by substituting hydrochloric acid for the hydrobromide acid used above. mula,

o NHl-HCI and is a white crystalline solid. The procedure used is as follows:

5 g. of o-methy1-p-nitro-a-acetamido-p-hydroxypropiophenone is heated under reflux with The hydrochloride salt is ob- It has the for- I 150 cc. of 10%.hydroch1oric acid for two hours.

The reaction mixture is evaporated to dryness in vacuo, the residual hydrochloride salt washed with absolute ethanol and collected. Purification by recrystallization from absolute ethanol yields the desired o-methyl-p-nltro-a-amino-phydroxypropiophenone hydrochloride as a white crystalline solid.

Example 3 5 g. of m-methoxy-p-nitro-a-p'-toluylamidop-hydroxypropiophenone is heated under reflux for three hours with 150 cc. of 10% hydrochloric acid. The reaction mixture is cooled, exhaustively extracted with ether to remove the pmethyl benzoic acid and the aqueous phase evaporated to dryness in vacuo. The crystalline residue obtained upon evaporation of the aqueous phase is m-methoxy-p-nitro-a-amino-phydroxypropiophenone hydrochloride of formula,

NorQ cn-cmon If desired, this white crystalline salt may be purifled by recrystallization from hot absolute ethanol.

The acetate salt of this product can be obtained by dissolving the solid hydrochloride in dilute acetic acid and adding at least one equivalent of sodium acetate to the solution.

Example 4 6 g. of 2-nitro-4,5-dimethy1--phenacetamidop-hydroxypropiophenone is heated under reflux with 150 cc. of 10% sulfuric acid for two hours. The reaction mixture is cooled, the phenylacetic acid removed by extraction with ether and the aqueous phase evaporated to dryness in vacuo to obtain the white, crystalline sulfate salt of 2- nitro 4,5 dimethyl-a-amino-fi-hydroxypropiophenone of formula,

Example 3 g. of 3-nitro-5-chloro-a-['-chloropropionamidol-p-hydroxypropiophenone is heated for two hours under reflux with 100 cc. of Irvdrochloric acid. The reaction mixture is evaporated to dryness in vacuo to obtain the desired 3- nitro 5 chloro a amino-fl-hydroxypropiophenone hydrochloride of formula,

By using the corresponding 5-bromo compound as the starting material one obtains 3-nitro-5- bromo-a-amino-fl-hydroxypropiophenone hydrochloride as a white crystalline solid.

Example 6 4 g. of 2-chloro-4-nitro-8-methyl-a-acetamido-p-hydroxypropiophenone is heated under reflux with 100 cc. of 10% hydrochloric acid for two hours. The reaction mixture is evaporated to dryness in vacuo to obtain the desired 2- chloro 4 nitro-6-methyl--amino-p-hydroxypropiophenone hydrochloride of formula,

4 OH: 0 NO -cn-omon The nltrophenyl ketonic N-acylamido alcohol and acyloxy compounds used as starting materials in the practice of the invention may be prepared as described in my copending applications Serial No. 45,976, filed August 24, 1948, and Serial No. 60,182, filed November 15, 1948, now abandoned. In said applications I have described and claimed a method for preparing the nitrophenyl ketonic N-acylamido alcohol compounds by the reaction of formaldehyde with an w-N-acylamidonitrophenylacetophenone in the presence of an alkaline catalyst. The following specific example showing the preparation of D- nitro a acetamido-fi-hydroxypropiophenone is illustrative of the general process used to prepare these starting materials.

11.1 g. of p-nitro-w-acetamidoacetophenone is mixed with 55 cc. of methanol and 17 cc, of 36-38% aqueous formaldehyde. 0.4 g. of=sodium bicarbonate is added and the mixture stirred at 35 C. for about one hour and a half during which time the solid product separates. I The mixture is cooled and stirred for one-half hour, the solid product collected, washed with water and dried at 60 C. The product thus obtained is p-nitroa-acetamido p hydroxypropiophenone; M. P. 166-7 C., which has the formula,

0 if I IH- -om NOrO-U-UH-CIIzOH i o oGtL-dn-cmo 0 cm What I claim is:

1. A compound of the class consisting of a free base and its acid addition salts, said free base having the formula,

Qg-cn-cmon R:

where R1 and R: are members of the class consisting of hydrogen, halogen, lower alkyl and lower alkoxy radicals.

2. An acid addition salt of p-nitro-a-amino-phydroxypropiophenone.

3. -Nitro-n-sm'ino p hsdroxypropiophenone hydrochloride.

4. An acid addition salt of o-methyl-p-nitroa-amino-fi-hydroxypropiophenone.

5. o Methyl p nitro a amino-p-hydroxypropiophenone hydrochloride.

6. An acid addition salt of m-methoxy-p-nitron-amino-p-hydroxypropiophenone.

6 'I. m Methon p nitro-a-amino-p-hydr propiophenone hydrochloride.

LOREN M. LONG.

No references cited. 

1. A COMPOUND OF THE CLASS CONSISTING OF A FREE BASE AND ITS ACID ADDITION SALTS, SAID FREE BASE HAVING THE FORMULA, 